Abstract
Although depression significantly impacts fitness, some hypotheses suggest that it may offer a survival benefit. However, there has been limited systematic investigation into the selection pressures acting on genes associated with depression at the genomic level. Here, we conducted comparative genomic analyses and computational molecular evolutionary analyses on 320 depression-associated genes at two levels, i.e., across the primate phylogeny (long timescale selection) and in modern human populations (recent selection). We identified seven genes under positive selection in the human lineage, and 46 genes under positive selection in modern human populations. Most positively selected variants in modern human populations were at UTR regions and non-coding exons, indicating the importance of gene expression regulation in the evolution of depression-associated genes. Positively selected genes are not only related to immune responses, but also function in reproduction and dietary adaptation. Notably, the proportion of depression-associated genes under positive selection was significantly higher than the positively selected genes at the genome-wide average level in African, East Asian, and South Asian populations. We also identified two positively selected loci that happened to be associated with depression in the South Asian population. Our study revealed that depression-associated genes are subject to varying selection pressures across different populations. We suggest that, in precision medicine-particularly in gene therapy-it is crucial to consider the specific functions of genes within distinct populations.